Process for the preparation of mixed anhydrides

ABSTRACT

The present invention is concerned with an improved process for the manufacture of mixed anhydrides. The process comprises adding an adjuvant base to a mixture of acid and reactive acid derivative. It is especially suitable for use in the synthesis of peptides and/or for the manufacture of pharmaceutically active substances or corresponding intermediates.

This application is a continuation of Ser. No. 08/976,800, filed Nov.24, 1997, now abandoned.

FIELD OF THE INVENTION

The present invention is in the field of the manufacture of mixedanhydrides.

BACKGROUND OF THE INVENTION

The manufacture of mixed anhydrides is known per se and is based on thereaction of an acid with a reactive acid derivative, for example an acidhalide or acid anhydride in the presence of an adjuvant base. Theproduction of mixed anhydrides has been described, for example, byBodansky in “Principles of Peptide Synthesis”, 2nd ed., published bySpringer Berlin, 1993, pages 21-29 and in “The Practice of PeptideSynthesis”, 2nd ed., published by Springer, Berlin, 1994 as well as byStelzel in Houben-Weyl, volume XV/2, “Methoden der organischen Chemie:“Synthese von Peptiden”, part II.

Mixed anhydrides play a role primarily in activating and couplingreactions. Thus, Bodansky (loc.cit.) describes the synthesis of mixedanhydrides with pivaloyl chloride for use in the synthesis of peptides.For example, for the production ofbenzyloxycarbonyl-α-methylalanyl-α-methylalanine methyl ester, acid andadjuvant base are provided and the acid chloride is added. The mixtureis stirred at −5° C. for 2 hours and subsequently at room temperaturefor 1 hour. The production ofbenzyloxycarbonyl-Nε-α-p-toluenesulphonyl-L-lysylglycine ethyl esterproceeds analogously.

Stelzel (loc. cit.) describes the synthesis ofN-benzyloxycarbonyl-L-prolyl-L-leucylglycine ethyl ester based on theaddition of isovaleroyl chloride to a mixture of Z-Pro-OH andtriethylamine in toluene.

However, these and other known processes for the production of mixedanhydrides have considerable disadvantages. Thus, the reaction does notproceed quantitatively by a long way. This is primarily due to theformation of byproducts, e.g. by disproportionation to the correspondingsymmetrical anhydrides. Consequently, it is necessary to subject thereaction mixture to a costly working-up and purification.

SUMMARY OF THE INVENTION

This invention provides a process for producing an anhydride of twodifferent carboxylic acids, comprising forming a mixture of a firstcarboxylic acid and a reactive acid derivative of a second carboxylicacid other than the first carboxylic acid, and reacting said mixture inthe presence of a base to produce said anhydride, said base being addedto said mixture to initiate the reaction.

By first mixing a carboxylic acid and the reactive acid derivative of adifferent carboxylic acid, and only afterwards combining the mixturewith the base, it has surprisingly been found that the formation ofunwanted byproducts including the symmetrical anhydrides can be largelyavoided. Consequently, the yield of the desired mixed anhydride isincreased. Because of the increased yield this invention provides a moreefficient reaction for producing mixed anhydrides. Additionally, theproduction of mixed anhydrides is rendered more economical since thereaction product is more pure and therefore requires less post-reactionpurification.

DETAILED DESCRIPTION OF THE INVENTION

This invention provides a process for producing an anhydride of twodifferent carboxylic acids, comprising forming a mixture of a firstcarboxylic acid and a reactive acid derivative of a second carboxylicacid other than the first carboxylic acid, and reacting said mixture inthe presence of a base to produce said anhydride, said base being addedto said mixture to initiate the reaction.

In accordance with this invention any of the conventional conditions forforming an anhydride by reacting a carboxylic acid, a reactive acidderivative, and a base, can be used. What is important is that the baseis not added until a mixture of the first carboxylic acid and thereactive acid derivative is formed.

Preferably the first carboxylic acid and the reactive acid derivativeare present in the mixture in a molar ratio of about 1:1, however eitherthe first carboxylic acid or the reactive acid derivative can be presentin excess. Preferably the base is present in the mixture in an amountwhich is at least about one mole per mole of the first carboxylic acid.More preferably, the base is present in an amount which is from aboutone mole to about two moles per mole of the first carboxylic acid. Stillmore preferably the base is present in an amount which is about one moleper mole of the first carboxylic acid. Preferably the base is present inthe mixture in an amount which is at least about one mole per mole ofthe reactive acid derivative. More preferably, the base is present in anamount which is from about one mole to about two moles per mole of thereactive acid derivative. Still more preferably, the base is present inan amount which is about one mole per mole of the reactive acidderivative.

This reaction is generally applicable and can be used for making anymixed anhydride. The first carboxylic acid and the second carboxylicacid can be any carboxylic acid provided that they are different fromeach other. The term “carboxylic acid” means any compound having a —COOHmoiety. These can be e.g. unsubstituted and substituted aliphatic,aromatic, aromatic-aliphatic, heteroaromatic or heteroaromatic-aliphaticcarboxylic acids or protected aminocarboxylic acids, e.g. N-acylatedaminocarboxylic acids such as natural N-acylated α-amino acids havingthe L-configuration or corresponding non-natural N-acylated α-aminoacids having the D-configuration as well as the corresponding racematesof the L- and D-amino acids. Moreover, homologues of such amino acidscan be used, e.g. amino acids in which the amino acid side-chain islengthened or shortened by one or two methylene groups and/or in which amethyl group is replaced by hydrogen. Furthermore, there can be usedsubstituted aromatic N-acylated α-amino acids, e.g. substitutedphenylanine or phenylglycine, which can carry one or more of thefollowing substituents—independently of one another—: alkyl, e.g.methyl, halogen, a protected hydroxy group, alkoxy, e.g. methoxy,alkanoyloxy, e.g. acetoxy, a protected amino or alkylamino group,alkyanoylamino, e.g. acetylamino or pivaloylamino, alkoxycarbonylamino,e.g. t-butoxycarbonylamino, arylmethoxycarbonylamino, e.g.benzyloxycarbonylamino or 9-fluorenylmethoxycarbonyl, and/or nitro.Moreover, benz-fused phenylalanine or phenylglycine, such asα-naphthylamine, or hydrogenated phenylalanine or phenyglycine, such ascyclohexylalanine or cyclohexylglycine, a 5- or 6-membered cyclicbenz-fused N-acylated α-amino acid, e.g. indoline-2-carboxylic acid or1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, also come intoconsideration. Furthermore, natural or homologous N-acylated α-aminoacids in which a carboxy group in the side-chain is present in aesterified or amidated form, e.g. as an alkyl ester group, such asmethoxycarbonyl or t-butoxycarbonyl, or as a carbamoyl group, analkylcarbamoyl group, such as methylcarbamoyl, or a dialkylcarbamoylgroup, such as dimethylcarbamoyl, and in which the amino group in theside-chain is present in acylated form, e.g. as an alkanoylamino group,such as acetylamino or pivaloylamino, as an alkoxycarbonylamino group,such as t-butoxycarbonylamino, can be used. In addition, amino acids inwhich a carboxy group in the side-chain is present as anaryl-methoxycarbonylamino group, such as benzyloxycarbonylamino, can beused. A hydroxy group in the side-chain can be present in a etherifiedor esterified form, e.g. as an alkoxy group, such as methoxy, and alsoas an arylalkoxy group, such as benzyloxy, or as a lower-alkanoyloxygroup, such as acetoxy. Suitable N-acyl groups are alkanoyl, such asacetyl or pivaloyl, alkoxycarbonyl, such as t-butoxycarbonyl andarylalkoxycarbonyl, such as benzyloxycarbonyl.

Examples of suitable unsubstituted and substituted aliphatic, aromaticand aromatic-aliphatic carboxylic acids, which can optionally be used inthe form of their protected derivatives, are propionic acid, isobutyricacid, (R)- and (S)-lactic acid as well as the corresponding racemates,2-phthalimidoxy-isobutyric acid and benzoic acid, 3,4-dihydroxybenzoicacid, salicylic acid, 1-naphthoic acid, 2-naphthoic acid, phenylaceticacid, p-hydroxyphenyl-acetic acid,(S)-α-[(t-butylsulphonyl)methyl]hydrocinnamic acid and(S)-α-[[[1-(morpholinocarbonyl)-1-methylethyl]sulphonyl]methyl]hydrocinnamicacid. 2-Pyridinecarboxylic acid, 3-pyridinecarboxylic acid,4-pyridinecarboxylic acid, 5-chloro-2-pyridinecarboxylic acid,2-pyrimidinecarboxylic acid, 4-pyrimidinecarboxylic acid,2-quinolinecarboxylic acid, 3-quinolinecarboxylic acid, 2-pyridyl-aceticacid, 3-indolylacetic acid, 3-(3-indolyl)propionic acid,isoquinoline-1-carboxylic acid and (4-imidazolyl)acetic acid can benamed as examples of suitable heteroaromatic or heteroaromatic-aliphaticcarboxylic acid.

Examples of suitable aforementioned amino acids, which optionally can beused in the form of their protected derivatives, are glycine, alanine,valine, norvaline, leucine, isoleucine, norleucine, serine, homoserine,threonine, methionine, cysteine, proline, trans-3- andtrans-4-hydroxyproline, phenylalanine, tyrosine, 4-nitrophenylalanine,4-aminophenylalanine, 4-chlorophenylalanine, β-phenylserine,phenylglycine, α-naphthylalanine, cyclohexylalanine, cyclohexyl-glycine,tryryptophan, indoline-2-carboxylic acid,1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, aspartic acid,asparagine, aminomalonic acid, aminomalonic acid monoamide, glutamicacid, glutamic acid mono-t-butyl ester, glutamine, N-dimethylglutamine,histidine, arginine, lysine, N-t-butoxycarbonyllysine, δ-hydroxylysine,ornithine, N-pivaloyl-ornithine, αγ-diaminobutyric acid orα,β-diaminopropionic acid and the like. Corresponding peptides whichconsist e.g of the aforementioned amino acids are also included.

Preferred carboxylic acids are the quinoline-2-carboxylic acids as wellas the protected aminocarboxylic acids of formula I

In which R is an amino protecting group. Especially preferred carboxylicacids are quinolinecarboxylic acids as well as acids of formula I inwhich R represents the benzyloxycarbonyl or tert.butoxycarbonylprotecting group, for example (S)-2-benzyloxy-carbonylamino-propionicacid or (S)-2-tert.-butoxycarbonylamino-propionic acid.

The described acids are commercially available or can be produced byreaction with reactive derivatives of the amino protecting groups.

The term “alkyl” denotes cyclic, branched or straight-chain alkyl groupswith 1-8, preferably 1-4, carbon atoms.

The term “aryl” or “aromatic” alone or in combination means the phenylor naphthyl group which can be optionally mono- or multiply-substitutedby alkyl, e.g. methyl, halogen, a protected hydroxy group, alkoxy, e.g.methoxy, alkanoyloxy, e.g. acetoxy, a protected amino or alkylaminogroup, alkanoylamino, e.g. acetylamino or pivaloylamino,alkoxycarbonylamino, e.g. t-butoxycarbonylamino,arylmethoxycarbonylamino, e.g. benzyl-oxycarbonylamino or9-fluorenylmethoxycarbonyl, and/or nitro. Substitution with akyl orhalogen is preferred and substitution with alkyl is especiallypreferred.

The term “cycloalkyl” means cyclic alkyl groups with 3 to 8 C atoms.

The term “halogen” denotes fluorine, chlorine, bromine and iodine.

The term “heteroaryl” refers to an aromatic 5- or 6-membered ring whichcan contain 1 or 2 atoms selected from nitrogen, oxygen or sulphur andwhich may have a substitution pattern as described earlier in connectionwith the term “aryl”.

The term “amino protecting group” refers to any protecting groupconventionally used to replace an acidic proton of an amino group whichcan be hydrolyzed to yield the amino group containing the acidic proton.Examples of such groups are described in Green, T., Protective Groups inOrganic Synthesis, Chapter 7, John Wiley and Sons, Inc. (1981), pp.218-287, herein incorporated by reference. The benzyloxycarbonyl and thetert.-butoxycarbonyl protecting groups are examples of such aminoprotecting groups. Other examples include carbamates, e.g.fluorenylmethyl, 2,2,2-trichloroethyl, 2-haloethyl,2-(trimethylsilyl)ethyl, t-butyl, allyl, benzyl. Further protectinggroups are 3,5-dimethoxybenzyl, p-nitro-benzyl, diphenylmethyl,triphenylmethyl, benzyl, formylj, acetyl, trifluoroacetyl,chloro-acetyl, the cyclic imides of N-phthaloyl, N-trimethylsilyl,N-benzenesulfonyl, N-toluenesulfonyl, N-p-methylbenzyl-sulfonyl.

The term “reactive acid derivatives” means acid halide, acid anhydrideor alkyl haloformate derivatives of carboxylic acids. Acid halidederivatives are preferred. The corresponding carboxylic acid chloridesand the corresponding protected aminocarboxylic acid chlorides, forexample alkanecarboxylic acid chlorides, are also preferred. Especiallypreferred are reactive derivatives such as anhydrides or acid halideswhich are derived from an acid R¹—COOH in which R¹ is alkyl, cycloalkyl,heteroaryl or aryl. Compounds in which R¹ is alkyl or aryl arepreferred; compounds in which R¹ is alkyl are especially preferred.Thus, the corresponding acid halides (R¹—C(O)Hal), especially thechlorides (the acid chlorides R¹—C(O)Cl), are preferred. Branchedaliphatic carboxylic acid halides, such as e.g. 2-ethylbutyryl chloride,cyclohexanecarboxylic acid chloride, 2,2-dimethyl-propionyl chloride(pivaloyl chloride) and isovaleroyl chloride, are preferably usedbecause of the steric and positive inductive effects. Furthermore,corresponding anhydrides can also be used the process in accordance withthe invention. Moreover, alkyl chloroformates, e.g. ethyl chloroformate,can be used. The especially preferred reactive acid derivatives arepivaloyl chloride, isovaleroyl chloride and ethyl chloroformate. Thecorresponding halides are commercially available or can be producedaccording to known methods. For example, the corresponding acidchlorides can be produced by reacting the acid with thionyl chloride,phosphorus trichloride or phosphorus pentachloride. Anhydrides can beproduced according to the process described in the Application. Theaforementioned alkyl chloroformates are commercially available or can beproduced according to known methods.

In accordance with this invention any conventional base utilized inanhydride formation reactions can be used in the reaction of thisinvention. Among the bases which can be utilized are the organic basessuch as the tertiary amines (both aliphatic and aromatic), or the alkaliand alkaline earth salts of the carboxylic acids used in the respectivereaction. Examples of tertiary amines include pyridine,N-alkylmorpholines, e.g. N-methyl- and N-ethylmorpholine, anddialkylanilines, such as dimethylaniline. Triethylamine is preferred. Inthe case of alkali and alkaline earth salts of the carboxylic acids, thesodium and potassium salts are preferred. The by far most preferredbases are tertiary amines, such as N-ethylmorpholine, dimethylaniline,triethylamine and N,N,N′,N′-tetramethylethylenediamine, especiallytriethylamine.

As used herein the term “pharmaceutically suitable salts” means saltsderived from metals, the ammonium salt, quaternary ammonium saltsderived from organic bases and amino acid salts. Examples of metal saltsare those derived from the alkali metals, for example lithium (Li+),sodium (Na+) and potassium (K+). Examples of quaternary ammonium saltsderived from organic bases include tetramethylammonium (N+(CH₃)₄),tetraethylammonium (N+(CH₂CH₃)₄), benzyltrimethylammonium(N+(C₆H₅CH₂)(CH₃)₃), phenyltriethylammonium (N+(C₆H₅)(CH₂CH₃)₃), and thelike. Those salts derived from amines include salts withN-ethylpiperidine, procaine, dibenzylamine,N,N′-dibenzylethylenediamine, alkylamines or dialkylamines as well assalts with amino acids such as, for example, salts with arginine orlysine. Other examples include hydrochlorides, sulfates, phosphates,lactates, and mesylates.

Any conventional inert solvent can be used as the solvent. Examples ofsuch inert solvents include tetrahydrofuran, toluene, hexane, acetone,dioxan, preferably lower carboxylic acid esters such as alkyl acetates,primarily methyl, ethyl and isopropyl acetate.

Advantageously, the reaction is carried out with temperature control atbetween −25 and +25° C., preferably between 0 and +5° C.

Anhydrides which can be manufactured according to the process inaccordance with the invention are likewise an object of the presentinvention. Thus, the present invention also embraces anhydrides of theformula

in which R is an amino protecting group and R¹ is alkyl, cycloalkyl,heteroaryl or aryl. Compounds in which R¹ is alkyl or aryl arepreferred; compounds in which R¹is alkyl are especially preferred.(S)-2-Benzyloxycarbonylaminopropionic acid-2,2-dimethylpropionic acidanhydride, (S)-2-tert.-butoxycarbonylamino-propionicacid-2,2-dimethylpropionic acid-anhydride and 2,2-dimethylpropionic acidquinoline-2-carboxylic acid anhydride are examples of these compounds.

The process described above is suitable, for example, for use in peptidesynthesis and/or for the manufacture of pharmaceutically activesubstances or corresponding starting materials or intermediates.

Thus, the present invention embraces a process for the manufacture of amixed quinoline-2-carboxylic acid anhydride of the formula

wherein R¹ is as defined above, in accordance with the describedprocess. Quinoline-2-carboxylic acid is thereby reacted with thecorresponding reactive acid derivative, e.g. an anhydride or preferablyan acid halide which is derived from the corresponding acid R¹—COOH. Thecorresponding acid chloride is preferred.

The resulting anhydride of formula II above can then be converted, forexample, into N-(2-quinolylcarbonyl)-L-asparagine (quinargine) byreaction with asparagine. Quinargine is known per se and is described,for example, in European Patent Application No. 611774. It is a valuableintermediate for the manufacture of pharmacologically active compounds.Thus, quinargine can be converted as described in Example 7 of theaforementioned European Patent Application into pharmacologically activecompounds which are suitable primarily for the treatment of viralinfections, especially such infections which are caused by HIV or otherretroviruses.

For the manufacture of quinargine according to the process describedabove, quinoline-2-carboxylic acid can be reacted with a reactivederivative of an acid R¹—COOH, in which R¹ is defined above, for examplewith pivaloyl chloride, and an adjuvant base, e.g. triethylamine. Thisreaction, which is described in detail in Example 1, yields thecorresponding mixed anhydride, here e.g. 2,2-dimethylpropionicacid-quinoline-2-carboxylic acid anhydride, which, after isolation oreven directly without further purification, can be reacted withasparagine in an aqueous, alkaline solution to give quinargine. Thereaction with asparagine preferably takes place in an aqueousNaOH/NaHCO₃ solution. With this processN-(2-quinolylcarbonyl)-L-asparagine (S-quinargine) can be manufactureddirectly from the educts in high yield without the isolation of anintermediate.

Furthermore, the present invention embraces the manufacture ofpharmaceutically active substances. For example, the aforementionedN-(2-quinolylcarbonyl)-L-asparagine can be converted by reaction with2-[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)carboxamide,which is known from European Patent Application No. 635,493, in thepresence of a coupling reagent such as e.g. a carbodiimide and aN-hydroxy compound, with the N-hydroxy compound being present in acatalytic amount. As described in Example 7 of European PatentApplication No. 611774, the aforementioned substances can be convertedin the presence of dicyclo-hexylcarbodiimide using a catalytic amount of1 -hydroxy-2(1 H)-pyridone in an inert solvent or solvent mixture suchas ethyl acetate/tetrahydrofuran intoN-t-butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-[[N-(2-quinolylcarbonyl)-L-asparaginyl]-amino]butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamideor into pharmaceutically suitable salts or corresponding esters derivedtherefrom.

Accordingly, the present invention also includes a process for themanufacture of these compounds. Such a process embraces in a first stepthe manufacture of a mixed anhydride and its conversion into quinargineas described above. The mixed anhydride, e.g. 2,2-dimethylpropionicacid-quinoline-2-carboxylic acid anhydride, can be obtained by adding anadjuvant base, e.g. triethylamine, to a mixture ofquinoline-2-carboxylic acid and a reactive acid derivative, preferablypivaloyl chloride. The resulting mixed anhydride is subsequently reactedwith asparagine in alkaline solution to giveN-(2-quinolylcarbonyl)-L-asparagine. This substance is then converted ina subsequent step with2-[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)carboxamideintoN-t-butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-[[N-(2-quinolylcarbonyl)-L-asparaginyl]-amino]butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamideas described above or optionally into a corresponding salt, preferablythe methanesulphonic acid salt, or into an ester.

Furthermore, by means of the process in accordance with a invention itis possible to convert an acid of formula I

with a reactive derivative of an acid R¹—COOH into an anhydride offormula III

wherein R is an amino protecting group as defined above and R¹ is alkyl,cycloalkyl, heteroaryl or aryl. Preferred processes are those in whichcompounds are used in which R¹ is alkyl or aryl; compounds in which R¹is alkyl are especially preferred. The amino protecting group can be aprotecting group known from the state of the art, such as, for example,as used in peptide chemistry. The benzyl-oxycarbonyl andtert.-butoxycarbonyl protecting groups are examples of such aminoprotecting groups.

Thus, using the process in accordance with the invention it is possibleto manufacture ethyl(S)-[1-(2-benzyloxycarbonylamino-propionyl)-piperidin-4-yloxy]-acetateand ethyl(S)-[1-(2-tert.butoxycarbonylamino-propionyl)-piperidin-4-yloxy]-acetate,which are also important pharmaceutical intermediates. As described inExamples 2 and 3, the corresponding intermediates can be obtained alsoin these cases in very good yields even without isolation of thecorresponding mixed anhydrides. In particular, the reaction is effectedby reacting a protected aminopropionic acid, e.g.(S)-2-benzyloxycarbonylamino-propionic acid or, respectively,(S)-2-tert.butoxycarbonylamino-propionic acid, with a reactive acidderivative as described above, here in both cases with pivaloylchloride, using a tertiary amine, here triethylamine, as the adjuvantbase. The amino protecting group of the aminopropionic acid can be anysuitable amino protecting group, with the benzyloxycarbonyl andtert.butoxycarbonyl protecting groups being preferred. The resultingmixed anhydrides (S)-2-benzyloxycarbonylaminopropionicacid-2,2-dimethylpropionic acid anhydride and(S)-2-tert.butoxycarbonylamino-propionic acid-2,2-dimethylpropionic acidanhydride can be reacted with ethyl (piperidin-4-yloxy)-acetate, e.g. ina potassium phosphate-buffered, aqueous ethyl acetate suspension, togive the aforementioned intermediates. These intermediates can beprocessed further to give pharmaceutically active substances.

For example, with the process in accordance with the invention it ispossible to use these intermediates for the manufacture of ethyl[Z]-(S)-[[1-[2-[[4-(amino-hydroximino-methyl)-benzoyl]amino]-1-oxopropyl]-4-piperidinyl]oxy]acetate,a fibrinogen receptor antagonist (Alig et al. (1992) J. Med. Chem. 35,4393-4407; Weller et al. (1996) J. Med. Chem. 39, 3139-3147). Theprocess described above can be performed as follows for the manufactureof this substance: The protecting groups can be cleaved off from theaforementioned intermediates and the amine obtained can be convertedwith a corresponding acid chloride and subsequent reaction withhydroxylamine into the desired substance. In particular, thebenzyloxycarbonyl protecting group can be cleaved off by hydrogenationand the tert.-butoxycarbonyl protecting group can be cleaved off by acidfrom, respectively, ethyl(S)-[1-(2-benzyloxycarbonylamino-propionyl)-piperidin-4-yloxy]-acetateand ethyl(S)-[1-(2-tert.-butoxycarbonylamino-propionyl)-piperidin-4-yloxy]-acetate.The liberated amine can then reacted with 4-cyanobenzoyl chloride, whichcan be prepared from thionyl chloride and 4-cyanobenzoic acid, andsubsequently converted by reaction with hydroxylamine hydrochloride andtriethylamine and working-up in acidic medium into ethyl[Z]-(S)-[[1-[2-[[4-(amino-hydroximino-methyl)-benzoyl]amino]-1-oxopropyl]-4-piperidinyl]oxy]acetatein accordance with Example 4.

Accordingly, the process in accordance with the invention also relatesto the manufacture of ethyl[Z]-(S)-[[1-[2-[[4-(amino-hydroximino-methyl)-benzoyl]amino]-1-oxopropyl]-4-piperidinyl]oxy]acetateby producing a mixed anhydride in a first step as described above andconverting it by reaction with a compound of formula IV

wherein R² represents an alkyl group, preferably ethyl or tert.-butyl,into an ester or formula V

wherein R and R² are as defined above. Subsequently, the aminoprotecting group R can be cleaved off and optionally the R² group can betrans-esterified to the ethyl ester, with the cleavage of the aminoprotecting group and the trans-esterification to the ethyl ester beingoptionally carried out simultaneously depending on the protecting groupused, e.g. in the case of the tert.-butyl protecting group by reactionwith H₂SO₄/ethanol. Subsequently, the resulting amine of formula VI

wherein R² is as defined above, can be reacted with 4-cyano-benzoylchloride to give the compound of formula VII

wherein R² is as defined above. Alternatively, when e.g. thebenzyloxycarbonyl protecting group is used, the cleavage of theprotecting group can be effected by hydrogenation, followed by reactionwith 4-cyanobenzoyl chloride and trans-esterification to thecorresponding ethyl ester (R²=ethyl). Of course, the corresponding ethylester may be introduced simultaneously as described in Example 4 viacompound IV with R²=ethyl. Subsequently, ethyl[Z]-(S)-[[1-[2-[[4-(amino-hydroximino-methyl)-benzoyl]amino]-1-oxopropyl]-4-piperidinyl]oxy]acetatecan be obtained by reacting hydroxylamine hydrochloride with thecompound of formula VII. If desired, the compound obtained can beconverted into a pharmaceutically suitable salt.

The following Examples illustrate the invention and do not have anylimiting character.

EXAMPLES Example 1 Manufacture of N-(2-quinolylcarbonyl)-L-asparagine(S-quinargine)

34.60 g (200 mmol) of quinoline-2-carboxylic acid (Benechim S. A.) weresuspended in 350 ml of ethyl acetate (Fluka) while stirring and under aprotective gas at 0 to 5° C. and treated with 25.0 ml (200 mmol) ofpivaloyl chloride (Fluka). 28.0 ml (200 mmol) of triethylamine (Fluka)were added to the white suspension within 30 minutes, with thetemperature being held at 0 to 5° C. Subsequently, the suspension wasstirred at 0 to 5° C. for 30 minutes. The white suspension was filteredand the filter cake was washed with 100 ml of cooled (0-5° C.) ethylacetate (Fluka). The filtrate contained the resulting2,2-dimethylpropionic acid-quinoline-2-carboxylic acid anhydride havingthe following characteristics: melting point: 47° C.; MS: [M+H]⁺258; IR:1750 cm⁻¹, 1775 cm⁻¹. The cooled (0-5° C.), light yellow filtrates werecombined and treated within 5 minutes while stirring intensively with apre-cooled solution of 30.0 g (200 mmol) of L-asparagine (Fluka), 8.0 g(200 mmol) of sodium hydroxide (Fluka) and 16.80 g (200 mmol) of sodiumbicarbonate in 350 ml of cold, deionised water (0-5° C.), with thetemperature being held at between 0 and 5° C. Subsequently, the coolingwas removed and the light green two-phase system was stirred at roomtemperature for about 17 hours. The aqueous phase of the now colourlesstwo-phase system was treated with 200 ml of methanol (Merck) whilestirring and under argon. Then, 49 ml of 25% hydrochloric acid (Merck)were added dropwise to pH 3.0. In so doing, the temperature rose to 28°C. and crystallization set in. The white suspension was stirred at roomtemperature for one hour, subsequently cooled to 0-5° C. and stirred atthis temperature for a further hour. The filtered-off filter cake waswashed with a total of 80 ml of cold, deionised water (0-5° C.) anddried in a rotary evaporator at 5° C./10 mbar for 6 hours. Yield: 47.52g (83%) of N-(2-quinolylcarbonyl)-L-asparagine in the form of whitecrystals [melting point: 209° C. (decomposition), HPLC analysis 99.8%(area)].

Example 2 Manufacture of Ethyl(S)-[1-2-2(benzyloxycarbonylaminopropionyl)-piperidin-4-yloxy]-acetate

55.8 g (250 mmol) of (S)-2-benzyloxycarbonylaminopropionic acid(obtainable from the corresponding aminocarboxylic acid by protection ofthe amino function with a benzyloxycarbonyl derivative; Bodansky et al.,1 oc. cit.) were dissolved in 560 ml of ethyl acetate (Fluka) whilestirring and under argon, cooled to 0 to 5° C. and treated with 31.0 ml(250 mmol) of pivaloyl chloride (Fluka). 35.0 ml of triethylamine(Fluka) were added dropwise to the light yellowish solution within 30minutes, with the temperature being held at 0 to 5° C. A whitesuspension formed. The white precipitate was filtered off through apre-cooled glass filter (G3) and the filter cake was washed with 140 mlof cold ethyl acetate (0 to 5° C., Fluka). To the combined filtrates, aclear, colourless liquid which contained the anhydride, were added 55.9g (250 mmol) of ethyl (piperidin-4-yloxy)-acetate hydrochloride(obtainable from the corresponding tert.-butyl compound (Alig et al.,loc. cit.) by trans-esterification with ethanol/hydrochloric acid) and66.6 g (250 mmol) of Na₃PO₄.3H₂O. The white suspension was treated at 5to 10° C. 500 ml of deionised water within 30 seconds under argon andwhile stirring vigorously, with the temperature rising to 20° C. Thecolourless two-phase system was stirred vigorously at 20 to 25° C. forone hour. Subsequently, the aqueous phase was separated and the organicphase was washed with 1M sodium bicarbonate solution and then with 1Naqueous ammonia solution. The organic phase was dried over about 50 g ofsodium sulphate, filtered and the filter cake was washed with about 100ml of ethyl acetate. The combined filtrates were evaporated in a rotaryevaporator and the oily residue was taken up with 100 ml of ethanol. Theclear solution was evaporated at 50°/20 mbar to give 90.2 g (92 wt. %)of ethyl(S)-[1-(2-benzyloxycarbonylaminopropionyl)-piperidin-4-yloxy]-acetate asa clear, colourless oil.

Example 3 Manufactureof(S)-[1-(2-tert.-butoxycarbonylaminopropionyl)-piperidin-4-yloxy]-acetate

47.3 g (250 mmol) of (S)-2-tert.-butoxycarbonylamino-propionic acid(Fluka) were dissolved in 560 ml of ethyl acetate (Fluka) while stirringand under argon, cooled to 0-5° C. and treated with 31.0 ml (250 mmol)of pivaloyl chloride (d=98; Fluka). The light yellowish solution wastreated dropwise within 30 minutes with 35.0 ml (250 mmol) oftriethylamine (d=0.726; Fluka), with the temperature being held in therange of 0-5° C. A white suspension formed. The white precipitate wasfiltered off through a pre-cooled, sintered glass filter (G3) and thefilter cake was washed with 140 ml of cold ethyl acetate (0 to 5° C.).To the combined filtrates, a light yellow solution, were added 55.9 g(17. HCl; 250 mmol) of ethyl (piperidin-4-yloxy)-acetate hydrochlorideand 66.6 g of K₃PO₄.3H₂O (250 mmol; Merck). The white suspension wastreated with 500 ml of deionised water at 5 to 10° C. under argon andwhile stirring vigorously, with the temperature rising to 20° C. Thecolourless two-phase system was stirred at 20 to 25° C. for two hours.The aqueous phase was separated and the organic phase was washed with500 ml of a 1M sodium bicarbonate solution. The organic phase was driedover about 50 g of sodium sulphate, filtered and the filter cake waswashed with about 100 ml of ethyl acetate. The combined filtrates wereevaporated in a rotary evaporator at 50°/20 mbar, giving 85.5 g (95 wt.%) of ethyl(S)-[1-(2-tert.-butoxycarbonylamino-propionyl)-piperidin-4-yloxy]-acetateas a crude product in the form of a clear, yellowish oil (HPLC analysis:88.9% (area).

Example 4 Manufacture of Ethyl[Z]-(S)-[[1-[2-[[4-(amino-hydroximino-methyl)-benzoy]amino]-1-oxopropyl]-4-piperidinyloxy]-acetate

For the manufacture of the aforementioned compound, 90.2 g (230 mmol) ofethyl(S)-(1-(2-benzyloxycarbonylamino-propionyl)-piperidin-4-yloxy]-acetatein 450 ml of ethanol were treated with 4.5 g of 10% palladium/charcoaland the resulting solution was hydrogenated while stirring intensivelyat a hydrogen pressure of 1.1 bar at 22 to 24° C. for 40 minutes. Afterevacuation the hydrogenation kettle was again filled and stirred for afurther 30 minutes. The suspension was subsequently filtered over 30 gof Speedex (Dicalite Speedex), the filter cake obtained was washed with450 ml of ethanol and the combined, clear filtrates were cooled to 0 to5° C. and treated with 32 ml (230 mmol) of triethylamine (230 mmol). Tothis solution was added while stirring a light yellow solution of 38 g(230 mmol) of 4-cyanobenzoyl chloride in 80 ml of toluene, with thetemperature being held at between 0 and 5° C. The light yellow solutionwas stirred at room temperature for one hour and then treated with 31.9g (460 mmol) of hydroxylamine hydrochloride (Fluka) and with 64 ml (460mmol) of triethylamine (Fluka), with the temperature rising to about 28°C. The white suspension was stirred at room temperature (20 to 25° C.)for 17 hours, with an almost clear suspension forming after one hour anda white precipitate forming thereafter. The white suspension was treatedwith 36 ml of 25% hydrochloric acid. The suspension was cooled to 0 to5° C., stirred for one hour, filtered through a pre-cooled sinteredglass filter (G3) and the filter cake was washed with 250 ml of coldethanol. Subsequently, it was dried to constant weight, giving 70.6 g(73 wt. %) of ethyl[Z]-(S)-[[1-[2-[[4-(amino-hydroximino-methyl)-benzoyl]amino]-1-oxopropyl]-4-piperidinyl]oxy]acetate. The powder was dissolved in amixture of 560 ml of ethanol and 140 ml of water under reflux and whilestirring and subsequently the solution was cooled to room temperaturewithin two hours and then stirred at a temperature of 0 to 5° C. for onehour. The solution was filtered through a pre-cooled glass filter (G3)and the filter cake was washed with a mixture of 140 ml of cold ethanol(0 to 5° C.) and 35 ml of cold water (0 to 5° C.); the product wassubsequently dried to constant weight at 50° C./20 mbar. The resultingwhite crystals (65.6 g; 68 wt. %) were suspended in a mixture of 528 mlof ethanol and 132 ml of water and treated with 3.3 g of active charcoal(Norit SX-1). The dark suspension was heated under reflux for 15minutes, cooled to 65 to 70° C. and added via a glass filter to apre-warmed funnel. The filtrates were stirred, with a precipitateseparating from 60° C. The white suspension was cooled to roomtemperature within three hours, then cooled to 0 to 5° C. and, afterstirring for one hour, filtered through a correspondingly pre-cooledsintered glass filter (G3). The filter cake was washed with a mixture of132 ml of cold ethanol and 33 ml of water (0 to 5° C.) and subsequentlydried to constant weight at 50° C./20 mbar. Yield: 60.15 g (55%); m.p.:212-213°; ee (HPLC)>99.9%; opt. rot. [α]₃₆₅ +223.5 (c=1.0; HCl).

Example 5 Manufacture of Additional Mixed Anhydrides

Additional compounds can be manufactured according to the process inaccordance with the invention analogously to Examples 1 to 3. Theresults of further reactions are compiled in the following Table.

Educt 1 Educt 2 Anhydride Coupling product

17.32 g 12.1 g IR: 1775, 1755 cm⁻¹ 25.73 g (90%)

CH₃SO₂Cl

1.73 g 1.15 g IR: 1782, 1739 cm⁻¹ 1.53 g (53%)

1.73 g 1.06 g IR: 1808, 1753 cm⁻¹ 1.59 g (61%)

1.73 g 1.20 g IR: 1812, 1756 cm⁻¹ 2.14 g (75%)

1.73 g 1.35 g IR: 1805, 1749 cm⁻¹ 2.0 g (74%)

1.73 g 1.47 g IR: 1807, 1753 cm⁻¹ 2.14 g (83%)

1.73 g 1.63 g IR: 1804, 1750 cm⁻¹ 2.2 g (77%)

1.73 g 1.41 g IR: 1795, 1731 cm⁻¹ 2.31 g (81%)

1.73 g 1.83 g IR: 1787, 1731 cm⁻¹

1.73 g 1.08 g IR: 1790, 1735 cm⁻¹ 1.64 g (57%)

55.8 g 30.14 g IR: 1817, 1750 cm⁻¹ 90.20 g (92%)

47.3 g 30.14 g IR: 1817, 1748 cm⁻¹ 85.50 g (95%)

What is claimed is:
 1. A process for producing an anhydride of twodifferent carboxylic acids, comprising forming a mixture of a firstcarboxylic acid and a reactive acid derivative of a second carboxylicacid other than the first carboxylic acid, and reacting the mixture inthe presence of a base to produce the anhydride, the base being added tothe mixture to initiate the reaction.
 2. The process of claim 1, whereinthe first carboxylic acid and the reactive acid derivative are presentin the mixture in a molar ratio of about 1:1.
 3. The process of claim 1,wherein the base is present in the mixture in an amount which is atleast about one mole per mole of the first carboxylic acid.
 4. Theprocess of claim 3, wherein the base is present in an amount which isfrom about one mole to about two moles per mole of the first carboxylicacid.
 5. The process of claim 4, wherein the base is present in anamount which is about one mole per mole of the first carboxylic acid. 6.The process of claim 1, wherein the base is present in the mixture in anamount which is at least about one mole per mole of the reactive acidderivative.
 7. The process of claim 6, wherein the base is present in anamount which is from about one mole to about two moles per mole of thereactive acid derivative.
 8. The process of claim 7, wherein the base ispresent in an amount which is about one mole per mole of the reactiveacid derivative.
 9. The process of claim 1, wherein the first carboxylicacid is selected from the group consisting of aliphatic carboxylicacids, aromatic carboxylic acids, aromatic-aliphatic carboxylic acids,heteroaromatic carboxylic acids, heteroaromatic-aliphatic carboxylicacids, and protected aminocarboxylic acids.
 10. The process of claim 1,wherein the aliphatic carboxylic acid is an alkanecarboxylic acid. 11.The process of claim 9, wherein the first carboxylic acid is a protectedaminocarboxylic acid.
 12. The process of claim 1, wherein the reactiveacid derivative is an acid halide, an acid anhydride, or an alkylhaloformate.
 13. The process of claim 12, wherein the reactive acidderivative is an acid halide.
 14. The process of claim 13, wherein theacid halide is pivaloyl chloride.
 15. The process of claim 13, whereinthe acid halide is isovaleroyl chloride.
 16. The process of claim 12,wherein the reactive acid derivative is an acid anhydride.
 17. Theprocess of claim 12, wherein the reactive acid derivative is an alkylhaloformate.
 18. The process of claim 17, wherein the alkyl haloformateis ethyl chloroformate.
 19. The process of claim 1, wherein the base isa tertiary amine, an alkali earth salt of the first carboxylic acid, oran alkaline earth salt of the first carboxylic acid.
 20. The process ofclaim 19, wherein the base is a tertiary amine.
 21. The process of claim20, wherein the tertiary amine is N-ethylmorpholine; dimethylaniline;triethylamine; or N,N,N′,N′-tetramethylethylenediamine.
 22. The processof claim 21, wherein the tertiary amine is triethylamine.
 23. Theprocess of claim 19, wherein the base is an alkali earth salt of thefirst car boxylic acid.
 24. The process of claim 19, wherein the base isan alkaline earth salt of the first carboxylic acid.
 25. The process ofclaim 1, wherein the first carboxylic acid is quinoline-2-carboxylicacid and the reactive acid derivative is a reactive acid derivative ofan acid of the formula R¹—COOH, wherein R¹ is alkyl, cycloalkyl,heteroaryl or aryl.
 26. The process of claim 25, wherein the base is atertiary amine.
 27. The process of claim 25, wherein the base is analkali earth salt of quinoline-2-carboxylic acid or an alkaline earthsalt of quinoline-2-carboxylic acid.
 28. The process of claim 25,wherein R¹ is alkyl.
 29. The process of claim 28, wherein R¹ is selectedfrom the group consisting of t-butoxy, isopropyl, isobutyl,1-ethylpropyl, cyclohexyl, and 1-ethylpentyl.
 30. The process of claim25, wherein R¹ is aryl.
 31. The process of claim 30, wherein R¹ isselected from the group consisting of phenyl and 2,4,6-trimethylphenyl.32. The process of claim 25, wherein R¹ is ethoxy.
 33. The process ofclaim 25, wherein the reactive acid derivative is a halide ofquinoline-2-carboxylic acid.
 34. The process of claim 33, wherein thereactive acid derivative is a chloride of quinoline-2-carboxylic acid.35. The process of claim 1, wherein the first carboxylic acid is aprotected aminocarboxylic acid of the formula

wherein R is an amino protecting group, and the reactive acid derivativeis a reactive acid derivative of an acid of the formula R¹—COOH, whereinR¹ is alkyl, cycloalkyl, heteroaryl or aryl.
 36. The process of claim35, wherein the base is a tertiary amine.
 37. The process of claim 36,wherein the base is triethylamine.
 38. The process of claim 35, whereinthe base is an alkali or alkaline earth salt of the acid of formula I.39. The process of claim 35, wherein R¹ is alkyl.
 40. The process ofclaim 39, wherein R¹ is t-butyl.
 41. The process of claim 35, wherein R¹is aryl.
 42. The process of claim 35, wherein R is benzyloxycarbonyl.43. The process of claim 35, wherein R is tert.butoxycarbonyl.
 44. Theprocess of claim 1, wherein the first carboxylic acid is(S)-2-benzyloxycarbonylamino-propionic acid, and the reactive acidderivative is a reactive acid derivative of 2,2-dimethyl-propionic acid.45. The process of claim 44, wherein the reactive acid derivative ispivaloyl chloride.
 46. The process of claim 44, wherein the base istriethylamine.
 47. The process of claim 1, wherein the first carboxylicacid is (S)-2-tert.-butoxycarbonylamino-propionic acid, and the reactiveacid derivative is a reactive acid derivative of 2,2-dimethyl-propionicacid.
 48. The process of claim 47, wherein the reactive acid derivativeis pivaloyl chloride.
 49. The process of claim 47, wherein the base istriethylamine.